Pain is a perceived nociceptive response to local stimuli in the body. The perception of pain at the level of the central nervous system requires the transmission of painful stimuli by peripheral sensory nerve fibers. Upon stimulation of tissue (i.e., thermal, mechanical or chemical), electro-chemical signals are transmitted from the sensory nerve endings to the spinal column, and hence to the brain where pain is perceived.
The ear is highly innervated with sensory afferents capable of transmitting various painful stimuli to the central nervous system. The ear is comprised of outer, middle and inner ear portions and otic pain may arise in any of these portions of the ear. Pain conditions involving the ear, therefore, can arise in numerous instances, such as: foreign body stimulus, inflammation, edema, otic congestion, otic pressure, infection, accidental trauma, surgical procedures and post-surgical recovery.
The outer or "external" ear is comprised of the pinna and external ear canal ("EAC"). The EAC is a tubular, slightly curved structure extending from the pinna to the tympanic membrane or "ear drum." Sound travels through the EAC and causes the tympanic membrane to vibrate. Various disorders can arise in the outer ear eliciting pain to the host. For example, otitis externa is an acute, painful inflammatory condition of the EAC that affects all age groups of humans and accounts for roughly half of the ear pain pathologies known to exist. During the summer months, cases of otitis externa tend to increase due to what is known as "swimmer's ear." Swimmer's ear generally arises from the seepage of water into the EAC during swimming and the onset of infection and pain. Other outer ear disorders causing pain to the host include insertion of foreign objects in the ear, cerumen impaction, long-term use of hearing aids, and dermatological disorders, including psoriasis, eczema and seborrhea.
The middle ear is an air-filled cavity between the outer and inner ears. The middle ear is separated from the outer ear by the tympanic membrane and abuts the inner ear. It has a volume of about two milliliters and is connected to the back of the throat via the eustachian tube. The middle ear contains the malleus, icus and stapes, which are tiny bones that translate the movement of the tympanic membrane to the inner ear. Various conditions of the middle ear can cause pain to the host. For example, otitis media, which can be acute ("AOM") or associated with effusion ("OME"), is an inflammatory condition of the middle ear which generally affects children more often than adults (Karver, Otitis Media, Primary Care, Volume 25, No. 3, pages 619-632 (1998). The etiology of otitis media is fairly broad and can be caused by various inflammatory events including infection and allergy. Effusion, which can be sterile or contain infectious material, may also result from otitis media. The fluid consists of various inflammatory cells (white blood cells), mediators of allergy and inflammation and cellular debris.
The inner ear comprises the sensory organs of the auditory and vestibular systems. It consists of two major compartments, known as the bony and membranous labyrinths. These chambers are highly organized and sensitive tissues and provide both auditory perception and balance to the animal. Various pathologies may arise in the inner ear, creating distortion of hearing, loss of balance and pain.
Since otic pain is often associated with infection and resultant congestion and pressure, the primary therapeutic approach to treating otic pain is the administration of antiobiotics, both systemically and topically.
Various other therapies have been attempted for the alleviation of otic pain. Topical steroids (e.g., hydrocortisone) and systemic non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, have been used typically in conjunction with anti-infectives to treat otic pain.
Local anesthetics are another class of compounds which relieve pain by directly inhibiting nerve cellular function. A drawback of local anesthetic therapy is the short duration of action of such drugs. Another problem with the use of local anesthetics is that their mechanism of action, non-specific membrane stabilization, can have the undesired coincident effect of also inhibiting biological functions of cells, such as fibroblasts and surrounding neural cells. Therefore, even though pain sensation can be abated with local anesthetic treatment, healing and normal function of the tissue may be significantly compromised. There is a need, therefore, to discover agents which potently and specifically inhibit the transmission of painful stimuli by sensory afferents, following local otic application.
Other agents have also been suggested for use in treating pain. Such agents include tricyclic antidepressants such as imipramine and desipramine, alpha-2 adrenergic agonists, serotonin uptake blockers, such as prozac, and other analgesics such as paracetamol, as described in U.S. Pat. No. 5,270,050 (Coquelet et al.). Some of these therapies, however, have been associated with side-effects such as dryness of mouth, drowsiness, constipation, and low potencies and efficacies.
Opiates are a class of compounds with well documented clinical analgesic efficacy. Opiates can be administered in a number of ways. For example, opiates can be administered systematically, by intravenous injection or oral dosage, or locally, by subcutaneous, intramuscular or topical application. Systemic administration of opiates, however, has been associated with several problems including dose escalation (tolerance), addiction, respiratory depression and constipation.
"Opioids" is a generic term of art used to describe molecules that produce morphine-like activity in the body. There are three major categories of opioid receptors, designated .mu. (mu), .kappa. (kappa) and .delta. (delta). Other sub-type receptors appear to exist as well. Opioid receptors have been differentiated among each other by the preferential binding affinities of different agonists and antagonists, and by the different responses obtained from each receptor's binding. For example, the full agonist morphine has a ten times greater affinity for the mu receptor than for the delta and kappa receptors. Thus, morphine is a mu agonist (See, Goodman and Gilman's Pharmacological Basis of Therapeutics (8th Edition), Jaffee, Chapter 21: Opioid Analgesics And Antagonists, page 485-492 (1993).) Kappa receptors have also been delineated from the general class of opioid receptors by the fact that mu and delta receptor agonists increase membrane potassium conductance and decrease the duration of presynaptic action potential, whereas kappa receptor agonists decrease voltage-dependent calcium conductance without affecting potassium conductance (Kanemasa, k-opioid agonist U50488 inhibits P-type Ca.sup.2+ channels by two mechanisms, Brain Research, volume 707, pages 207-212 (1995)).
While it is known that opiate analgesics such as morphine relieve pain by activating specific receptors in the brain, recent studies demonstrate the analgesic effects of compounds which act on kappa receptors in peripheral tissue. (See, Joris et al., Opiates suppress carrageenan-induced edema and hypothermia at doses that inhibit hyperalgesia, Pain, volume 43, pages 95-103 (1990); Eisenberg, The peripheral antinociceptiave effect of morphine in a rat model offacial pains, Neuroscience, volume 72, No. 2, pages 519-575 (1996); and Gohschlich, The peripherally acting k-opiate agonist EMD 61753 and analogues: opioid activity versus peripheral selectivity, Drugs Exptl. Clin. Res., volume XX1(5), pages 171-174 (1995)).
Nowhere in the art, however, has it been described to use kappa opioid agonists to treat otic pain.